Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, None, Parkinson's Disease Dementia
Reference Assembly: GRCh37 (105)
Position: Chr1:227073271 C>T
dbSNP ID: rs63750197
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TCG to TTG
Reference Isoform: PSEN2 isoform 1 (448 aa)
Genomic Region: Exon 5


The S130L variant has been detected in people with Alzheimer's disease, including those with an early-onset presentation. However, this variant has not been shown to segregate with disease. Although pathogenicity is currently unclear, S130L has been classified as "probably pathogenic" according to an algorithm proposed by Guerreiro et al., 2010 (Lohmann et al., 2012). The S130L variant is also associated with dilated cardiomyopathy in at least two families, although penetrance is incomplete (Li et al., 2006).

The S130L variant was first reported in a kindred from northern Italy (FL056) (Sorbi et al., 2002; Tedde et al., 2003). The proband experienced symptom onset, chiefly memory loss, at age 65. The proband had a family history of dementia, with an affected mother, uncle, and grandfather. Onset age was 65 for the mother and uncle, and unknown for the grandfather. In this family the clinical presentation was characterized by a long disease duration, with many years of mild cognitive impairment before the development of bona fide dementia. Segregation with disease could not be determined.

This variant was also identified in a patient with apparent late-onset, sporadic AD (Tomaino et al., 2007). This patient had disease onset at age 81 with progressive memory impairment and spatial disorientation, as well as mood and personality changes. He rapidly developed language deficits, agitation, delusions, hallucinations, agnosia, aphasia, and mild bradykinesia. Two of the proband's siblings were reported to have Parkinson's disease, but were cognitively healthy. Segregation with disease could not be determined.

The S130L variant was detected in a Turkish individual who developed late-onset AD (Lohmann et al., 2012). His symptoms started at age 77, with depression, progressive memory impairment, and episodes of spatial disorientation. He also developed mild bradykinesia. His mother and maternal uncle were also affected by memory problems. Segregation with disease could not be determined.

The S130L variant was also one of several rare variants detected by exome sequencing in a British cohort composed of 47 unrelated, early onset AD cases and 179 elderly controls free of AD pathology. The variant was detected in one AD case and one control case. The AD patient developed cognitive symptoms at age 61 and died at age 65 with autopsy-confirmed AD. The precise age of the elderly control case was not reported (Sassi et al., 2014).

This variant was also reported in an individual with idiopathic Parkinson’s disease with dementia (Schulte et al., 2015). This individual first developed symptoms at age 73, beginning with bradykinesia. Later symptoms included resting tremor, rigor, postural instability, and dementia.

In a recent study using whole-exome sequencing, this variant was identified in three of 424 French people with early onset AD (Nicolas et al., 2015). Associated clinical data were limited for these individuals. Two of the S130L carriers had apparently sporadic AD with onset at ages 51 and 62, respectively. The third individual had a family history of dementia; however, segregation with disease could not be assessed. This individual was 65 at onset and had an APOE genotype of E3/E3.

In addition to the germ-line mutations described above, this variant was also one of three mosaic mutations detected in AD-related genes in the brain by deep sequencing (Sala Frigerio et al., 2015). Of the 130 entorhinal cortex samples analyzed, the S130L variant was detected in one control sample at an allelic frequency of about 1 percent. This individual died at age 90 with mild AD pathology (modified Braak stage II). The significance of a low frequency mosaic mutation in the brain is currently unclear.


At least one affected mutation carrier had neuropathology consistent with AD at autopsy (Sassi et al., 2014).

Biological Effect

When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the S130L variant did not affect levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2, indicating that the substitution does not alter steady-state endoproteolytic activity. When co-transfected with APP carrying the Swedish mutation, the S130L mutation did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005). Calcium signaling was altered in cultured skin fibroblasts from mutation carriers. Specifically, the resting intracellular calcium concentration was elevated (Li et al., 2006).

The S130L variant has been predicted to be "possibly damaging" by in silico analysis (Sassi et al., 2014; Lohmann et al., 2012).

Last Updated: 25 Sep 2015


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Paper Citations

  1. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  2. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  3. . Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24 PubMed.
  4. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiol Aging. 2002 Jul-Aug;23(1S):312.
  5. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  6. . Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease. J Neurol. 2007 Mar;254(3):391-3. PubMed.
  7. . Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 PubMed.
  8. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  9. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  10. . Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.

Other Citations

  1. Sala Frigerio et al., 2015

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiol Aging. 2002 Jul-Aug;23(1S):312.
  2. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.


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